Synthesis and evaluation of 3-[(2,4-Dioxo-1,3,8-triazaspiro[4.6]undec-3-yl) methyl]benzonitrile derivatives as potential anticonvulsants

Article abstract of DOI:10.1002/ardp.201200400

New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8-37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-electron donor. A series of 3-[(2,4-Dioxo-1,3,8-triazaspiro[4. 6]undec-3-yl)methyl]-benzonitrile derivatives 8-37 were synthesized and evaluated for their anticonvulsant activity. The most promising compounds 11, 18, 31, and 32 showed significant and protective effects on seizure. The novel anticonvulsant agents include essential pharmacophoric elements in their structure.

Full text of DOI:10.1002/ardp.201200400

200
Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Full Paper
Synthesis and Evaluation of 3-[(2,4-Dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile Derivatives as
Potential Anticonvulsants
Malavalli Madaiah1, Maralekere K. Prashanth1, Hosakere D. Revanasiddappa1, and Bantal Veeresh2
1 Department of Chemistry, University of Mysore, Manasagangotri, Mysore, India
2 Department of Pharmacology, G Pullareddy College of Pharmacy, Mehdipatnam, Hyderabad, India
New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8–37 were
synthesized and their pharmacological activities were determined with the objective to better
understand their structure–activity relationship (SAR) for anticonvulsant activity. All the
compounds were evaluated for their possible anticonvulsant activity by maximal electroshock
seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant
and protective effect on seizure, when compared with the standard drug valproate. The same
compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity
than the reference drug. From this study, it is quite apparent that there are at least three parameters
for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-
electron donor.
Keywords: Anticonvulsant / Maximal electroshock seizure / Neurotoxicity / Triazaspirobenzonitriles
Received: October 20, 2012; Revised: November 28, 2012; Accepted: November 30, 2012
DOI 10.1002/ardp.201200400
Introduction
on its efficacy for the specific type of seizures, tolerability,
and safety [6, 7]. Therefore, it is essential to search for newer
chemical entities for the treatment of epilepsy. Quite
recently, spirohydantoin analogs have become an emerging
new class of potent anticonvulsants [8].
Epilepsy, with an incidence of 0.5–1% of the population, is
second only to stroke as the most common derangement of
the central nervous system [1]. Many patients have seizures
that are resistant to the available medical therapies.
Although 70–80% of epileptics are currently controlled by
a variety of drugs, seizure protection is often accompanied by
numerous side effects including drowsiness, ataxia, gastro-
intestinal disturbances, gingival hyperplasia, hirsutism, and
megaloblastic anemia [2, 3]. Over the years, there has been
considerable success in the development of novel antiepilep-
tic drugs (AED) along with new improved formulations. These
include older ‘‘first generation’’ drugs such as carbamaze-
pine, phenobarbitol, valproic acid, and newer, ‘‘second gener-
ation’’ drugs such as lamotrigine, vigabatrin, tiagabine,
Hydantoins, a class of cyclic imides, have been demon-
strated to possess good anticonvulsant property [9, 10].
Depending on the nature of substitution on the hydantoin
ring, a wide range of other pharmacological properties, e.g.,
antihypertensive [11], herbicidal [12], antitumor [13], anti-HIV
[14], antibacterial [15] and antiviral [16] activities, have also
been identified.
In this study, the authors have reported the synthesis of a
new class of spirohydantoin analogs, such as 1,3,8-triazaspir-
ohydantoins as anticonvulsant agents.
topiramate, gabapentin, and levetiracetam [4, 5]. The selec- Results and discussion
tion of an antiepileptic drug for the treatment is predicated
Chemistry
The synthetic pathway being utilized in the preparation of 3-
Correspondence: Hosakere D. Revanasiddappa, Department of
Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
E-mail: hdrevanasiddappa@yahoo.com
Fax: þ91 821 2419363
[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzoni-
trile derivatives is outlined as shown in Scheme 1. The
synthesis begins by protection [17] of piperidin-4-one hydro-
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Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Novel Triazaspirobenzonitriles as Potential Anticonvulsants
201
Scheme 1. Synthetic pathway of targeted compounds 8–37. Reagents and conditions: (a) Boc anhydride, triethylamine, dichloro-
methane, rt, 16 h; (b) BF3 etherate, ethyl diazoacetate, ether, ꢀ208C, 1 h; (c) lithium hydroxide, tetrahydrofuran, water, 808C, 18 h;
(d) ammonium carbonate, sodium cyanide, ethanol/water, 208C, 24 h, 508C, 24 h; (e) anhydrous potassium carbonate, 3-(bromomethyl)-
benzonitrile, acetonitrile, reflux, 6 h; (f) dioxane in HCl, 208C, 4 h, sodium carbonate solution, 208C,1 h; (g) R ¼ sulfonyl chloride/acid
chloride, triethylamine, dichloromethane, 208C, 16 h.
chloride 1 with di-tert-butyl dicarbonate (Boc anhydride)
using dry dichloromethane as a solvent. The increase of
the carbon chain length [18] was carried out by BF3 etherate,
ethyl diazoacetate, and ether as solvent at ꢀ208C to form
seven membered ring 3. The hydrolysis and decarboxylation
[19] were carried out using lithium hydroxide, tetrahydro-
furan and water as the solvents to get compound 4. Under
Bucherer-Bergs condition [20, 21], construction of azaspiro
bicyclic hydantoin 5 was made. The reaction was carried out
in aqueous ethanolic media using sodium cyanide and
ammonium carbonate at heating temperature. The introduc-
tion of the substituent aryl groups at N-3 position of hydan-
toin ring was achieved via selective N-alkylation reaction by
reacting aryl halide in presence of potassium carbonate and
acetonitrile solvent [22, 23]. Target key intermediate 7 was
accomplished by deprotection of Boc group from compound
6 with dioxane in HCl and followed by basification with
sodium carbonate solution [24]. The aim of the 7 was intro-
duced to respective sulfonyl chlorides/acid chlorides at the N-
position of triazaspiro bicyclic moiety to lead to the desired
compounds 8–37 for structure–activity relationship (SAR)
study [25, 26]. This was furnished by normal condensation
reaction with good yield. The formation of the hydantoin
ring was confirmed by 1H NMR and mass spectra. The N-
substitution of substituted 3-[(2,4-dioxo-1,3,8-triazaspir-
o[4.6]undec-3-yl)methyl]benzonitrile with different acid
chlorides and sulfonyl chlorides was confirmed by the dis-
appearance of the NH group in 1H NMR, mass spectra, and IR
data. The products obtained were purified by column
chromatography using dichloromethane/methanol as an elu-
ent. The chemical structures, physical data, and yield of all
the synthesized compounds are given in Table 1.
Pharmacology
In past years, the discovery and development of anticonvul-
sant drugs has been the noticeable research field. The search
for new compounds combining strong anticonvulsant
activity is in progress. Many amide and sulfonamide deriva-
tives were prepared as potent anticonvulsant drugs and the
SAR studies have been reported [27]. In the present study, the
anticonvulsant activities of 30 newly synthesized triazaspir-
ohydantoin derivatives such as amides and sulfonamides
were determined using chemically induced PTZ and electri-
cally induced MES model of seizures.
The screening was performed at 1.0 mmol/kg of all syn-
thesized compounds. The results are presented in Table 2.
The preliminary anticonvulsant screening showed that com-
pounds 22, 23, 24, 29, 34, and 36 were inactive; however,
many of these compounds were active against PTZ at
1.0 mmol/kg, among which compounds 11, 18, 31, and 32
presented 100% protection. Compounds 16, 19, and 33
offered 66% protection. Compounds 8, 9, 10, 12, 13, 15, 16,
17, 19, 20, 25, 26, 27, 28, 30, 32, 33, and 35 showed moderate
protective effect in the MES and compounds 11, 18, and 31
were found to be 100% protective. Majority of the com-
pounds, except 22, 23, 24, 29, 34, and 36, were active in
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M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Table 1. Chemical structure, yield and melting point of the
compounds 8–37.
Table 2. Anticonvulsant activity of the new synthesized compounds
(1.0 mmol/kg) and valproate (300 mg/kg).
Compound
R
Yield
(%)
m.p.
(8C)
Compounds
MESa)
(% protection)
PTZb)
(% protection)
8
9
3,4-(H3C)2C6H3SO2
2-H3CC6H4SO2
3-BrC6H4SO2
67
67
65
69
68
69
68
70
68
63
67
67
63
68
65
68
65
72
67
71
70
70
72
71
68
73
68
68
67
68
182
180
194
188
180
182
198
192
184
182
189
180
184
181
224
202
204
186
189
195
187
198
181
196
195
187
199
214
199
192
Valproate
8
9
100
60
50
50
100
66
55
33
65
67
56
100
62
59
43
0.0
0.0
0.0
56
47
66
57
0.0
66
100
66
50
0.0
51
0.0
45
100
47
33
30
100
39
31
0.0
44
66
41
100
66
31
28
0.0
0.0
0.0
39
33
33
31
0.0
45
100
100
66
0.0
27
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2-FC6H4SO2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2,5-(H3C)2C6H3SO2
4-H3CC6H4SO2
3-ClC6H4SO2
4-F,2-H3CC6H3SO2
4-H3COC6H4SO2
4-H3CC6H4 CH2SO2
3-FC6H4SO2
3,5-(H3C)2C6H3SO2
4-H5C2C6H4SO2
3-H3CC6H4SO2
2-NCC6H4SO2
2-ClC6H4CH2ONHCO
4-ClC6H4ONHCO
4-CH3C6H4NHCO
C6H5CH2NHCO
2-FC6H4NHCO
3-CH3C6H4NHCO
3-ClC6H4NHCO
C6H5NHCO
3-FC6H4NHCO
4-FC6H4NHCO
C6H5ONHCO
4-ClC6H4NHCO
2-CF3C6H4NHCO
2-ClC6H4NHCO
4-(CH3)3CHC6H4NHCO
0.0
25
a)
Maximal electroshock seizure test.
Pentylenetetrazol test.
b)
MES tests making them useful for a broad spectrum of seizure
types. The bioactivity in the MES test, exhibited by sulfona-
mide and amide derivatives such as 8–37, when the hydrogen
group at the N-position was replaced by a phenyl ring, sub-
stitution of a small lipophilic group like fluoro group to the
phenyl ring increases the anticonvulsant activity of 11, 18, 31,
and 32.
better activity than that of valproate, which is a commer-
cially available drug. It showed a protective index (PI) of 3.07,
which was twofold higher compared to valproate having the
PI value 1.54. Table 3 reveals an ED50 of 0.33 mmol/kg and a
TD50 of 0.58 mmol/kg for 18, as compared with 0.47 and
0.68 mmol/kg, respectively, for 32. Thus, the PI of 18 is
slightly greater than the PI of 32. Compound 32, with an
ED50 value of 0.47 mmol/kg, was a little weaker than val-
proate, and it possessed lower neurotoxicity with PI value
of 1.44.
The compounds that exhibited significant activity were
subsequently subjected to a quantitative determination of
the median effective dose (ED50) and toxic dose (TD50) in mice.
Results of the quantitative test for selected compounds, along
with the data on the current antiepileptic drugs, are shown in
Table 3. Interestingly, the ED50 values of the selected com-
pounds were found to be smaller compared to the reference
anticonvulsant drug at molar doses. Among the tested com-
pounds, 3-[(2,4-dioxo-8-(3-fluorophenyloyl)-1,3,8-triazaspiro[4.6]-
undec-3-yl)methyl]benzonitrile (31) was the most active and
promising compound in this work. It possessed strong ED50
of 0.22 mmol/kg and TD50 of 0.70 mmol/kg in the PTZ-
induced seizure. This compound 31 was found to exhibit
MES and PTZ model of seizures were most widely used in
the search for new AEDs, suggesting that it really possesses a
good anticonvulsant profile. PTZ is a most frequently used
substance as well as an acute experimental model in the
preliminary screening to test potential anticonvulsant drugs.
The mechanism by which PTZ is believed to exert its action is
by acting as an antagonist at the GABA receptor complex.
Several biochemical hypotheses have been advanced involv-
ing the inhibition of the GABAergic system and the system of
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Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Novel Triazaspirobenzonitriles as Potential Anticonvulsants
203
Table 3. Comparison of the anticonvulsant activity (ED50), acute neurotoxic effects (TD50), median lethal dose (LD50), therapeutic and
protective indexes of the most promising anticonvulsant new synthesized compounds and standards in mice.
Compound
ED50
(mmol/kg)
TD50
(mmol/kg)
LD50
(mmol/kg)
Therapeutic
index
Protective
index
Valproate
1.65
0.24
0.33
0.22
0.47
2.56
0.56
0.58
0.70
0.68
3.00
1.10
0.91
1.17
1.04
1.81
4.42
2.73
5.16
2.19
1.54
2.26
1.75
3.07
1.44
11
18
31
32
ED50 ¼ median effective dose providing anticonvulsant protection in 50% of mice against pentylenetetrazole (PTZ) induced seizures.
TD50 ¼ median toxic dose producing minimal neurological toxicity in 50% of mice subjected to the Chimney test.
LD50 ¼ median lethal dose that causes 50% mortality in mice.
Therapeutic index ¼ LD50/ED50
.
Protective index ¼ TD50/ED50
.
the excitatory amino acid glutamate and aspartate [28]. It was
reported that the MES test was correlated to the generalized
tonic–clonic seizures and to a certain extent, partial convul-
sions in humans and, the PTZ test to the generailized absence
seizure [29]. So, these two kinds of seizure tests are very
meaningful for clinical prediction of the anticonvulsant drug
candidates.
for good anticonvulsant activity as suggested by Dimmock
and Baker.
A scrutiny for certain selected structures for active anti-
convulsants has been shown to possess a hydrophobic unit
(R), an electron donor group (D), and a hydrogen donor–
acceptor unit (HBD). In the present study, a series of the
active compounds possess all these requirements, which
are essential for anticonvulsant activity as proposed by
Dimmock and others. Thus, our new proposal for a pharma-
cophore model includes not only three factors but also an
additional hydrophobic binding site R shown in Fig. 1 for
bioactivity. From the results of this study, the following
structure–activity relationships could be derived. On the
one hand, the substitution pattern at different positions of
the sulfonamide and amides was compared with fluoro (11,
18, 27, 31, and 32) versus chloro (14, 23, 24, 29, 34, and 36). This
emphasises that the lipophilic fluorine on the phenyl ring
plays a key role in the anticonvulsant activity and chloro
decreases the activity. On the other hand, the cyano (22)
electron withdrawing moiety is practically inactive in both
the MES and PTZ tests.
For several decades, antiepileptic drugs research has
focused on identifying new potential drugs based on their
anticonvulsant activity against single acute seizures induced
by various stimulators, usually in mice. All established anti-
epileptic drugs have anticonvulsant activity in at least the
MES model [30]. Thus, this test may, in some way distinguish
the potential utility of compounds against different seizure
types. Hence, there is an increase in anticonvulsant activity
by our molecular modifications in the sulfonamide and
amide series anticonvulsants. Dimmock et al. [31, 32] has
proposed a binding site hypothesis for these compounds
eliciting anticonvulsant activity.
All the synthesized title compounds were comprised of the
essential pharmacophoric elements (Fig. 1) that are necessary
Figure 1. The essential structure elements for the pharmacophore of Dimmock and Baker are indicated by rectangles.
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204
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Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
ꢀ208C. Borontrifluoroetherate (4.81 g, 33.93 mmol) and ethyl
diazoacetate (4.50 g, 39.15 mmol) were added dropwise simul-
taneously, stirred for 1 h. After completion of the reaction (TLC),
it was brought to 08C and 30% potassium carbonate solution was
added till it was basic. The reaction mixture was extracted with
ethylacetate (3 ꢁ 50 mL), dried over Na2SO4 and concentrated
in vacuo to give the crude product which was purified by column
chromatography over silica gel (60–120 mesh) using hexane/
ethylacetate (7:3) as an eluent to get pure product 3. Colorless
liquid: (4.80 g, 64%); 1H NMR: 400 MHz, DMSO-d6: d 4.24 (q,
J ¼ 9.40 Hz, 2H), 3.73 (t, J ¼ 8.67 Hz, 1H), 3.54–3.56 (m, 4H),
2.56–2.62 (m, 4H), 1.44 (s, 9H), 1.30 (t, J ¼ 9.23 Hz, 3H); MS:
m/z 270.3 (Mþ), 271.3 (Mþ1); Anal. calcd. for C13H20NO5: C,
61.95; C, 57.76; H, 7.46; N, 5.18%. Found: C, 57.71; H, 7.40; N,
5.12%.
Conclusion
In conclusion, anticonvulsants have greatly improved the
lives of people with epilepsy. Approximately 70% of patients
can achieve complete freedom from seizures with appropri-
ate treatment [33]. From this study, it is quite apparent that
there are at least four parameters for the activity of anti-
convulsant drugs, which are, (i) a lipophilic domain, (ii) a
distal hydrophobic center, (iii) a two-electron donor system,
and (iv) a hydrogen donor–acceptor unit. Lipophilicity
appears to govern the MES and PTZ activity. If there is a
lipophilic moiety, then MES activity is favored. The synthes-
ized compounds confirmed all the four pharmacophore
model requirements for their activity. Compounds 11, 18,
31, and 32 with fluorine group showed anticonvulsant
activity in MES and PTZ tests as compared with compounds
without fluorine substituents. These four compounds also
showed optimum lipophilicity and lesser neurotoxicity than
some standard drugs. They may act as lead molecules for
future investigations.
Synthesis of tert-butyl 4-oxoazepane-1-carboxylate (4)
Reactants of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate 3
(4.8 g, 16.82 mmol) in tetrahydrofuran (20 mL) and lithium
hydroxide (2.41 g, 100.94 mmol) in water (7 mL) were mixed
and the reaction mixture was heated to 808C for 18 h and cooled
to room temperature. After completion of the reaction (TLC), the
reaction mixture was extracted with ethylacetate (3 ꢁ 50 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo to give
the crude product which was purified by column chromatog-
raphy over silica gel (60–120 mesh) using hexane/ethylacetate
(6:4) as an eluent to get pure product 4. White color solid: (3.3 g,
92%); m.p.: 1458C; 1H NMR: 400 MHz, DMSO-d6: d 3.57–3.59 (m,
4H), 2.64–2.66 (m, 4H), 1.66–1.68 (m, 2H), 1.45 (s, 9H); MS: m/z
213.3 (Mþ), 214.3 (Mþ1); Anal. calcd. for C11H19NO3: C, 61.95; H,
8.98; N, 6.57%. Found: C, 61.95; H, 8.98; N, 6.57%.
Experimental
Chemistry
Melting points were determined in one end open capillary tubes
on a Buchi 530 melting point apparatus and are uncorrected. The
1H NMR spectra were recorded on a Bruker Avance ꢀ400 MHz
NMR instrument using TMS as an internal standard and DMSO-d6
as a solvent. Chemical shifts are given in parts per million
(d-scale) and coupling constants are given in Hertz. Mass spectra
were recorded on a Perkin–Elmer LC–MS PE Sciex API/65 spectro-
photometer. IR spectra were recorded using KBr on a 8400S
Shimadzu Fourier Transform spectrophotometer (nmax in
cmꢀ1). Silica gel column chromatography was performed using
Merck 7734 silica gel (60–120 mesh), and Merck pre-coated TLC
plates were used. Elemental analysis (C, H, and N) was under-
taken with a Perkin–Elmer model 240C analyzer.
Synthesis of tert-butyl 2,4-dioxo-1,3,8-
triazaspiro[4.6]undecane-8-carboxylate (5)
Accurately weighed amount of tert-butyl 4-oxoazepane-1-carboxy-
late 4 (3.3 g, 15.47 mmol) in ethanol (25 mL) and ammonium
carbonate (2.52 g, 34.03 mmol) were taken in water (25 mL). A
solution of sodium cyanide (1.6 g, 32.79 mmol) in water (10 mL)
was added dropwise and the reaction mixture was stirred at
room temperature for 24 h at 508C and cooled to room tempera-
ture. After completion of the reaction (TLC), solid was filtered,
washed with water, and dried in vacuo to get hydantoin 5. White
color solid: (3.8 g, 86%); m.p.: 2198C; 1H NMR: 400 MHz, DMSO-d6:
d 10.63 (s, 1H), 8.41 (s, 1H), 3.45–3.69 (m, 2H), 3.06–3.18 (m, 2H),
1.79–1.82 (m, 3H), 1.67–1.67 (m, 3H), 1.40 (s, 9H); MS: m/z 283.3
(Mþ), 284.3 (Mþ1); Anal. calcd. for C13H21N3O4: C, 55.11; H, 7.47;
N, 14.83%. Found: C, 55.07; H, 7.42; N, 14.85%.
Synthesis of tert-butyl 4-oxopiperidine-1-carboxylate (2)
A mixture of piperidin-4-one hydrochloride 1 (4 g, 29.49 mmol),
triethylamine (5.96 g, 58.99 mmol), and Boc anhydride (7.08 g,
32.44 mmol) in dry dichloromethane (40 mL) was stirred at
room temperature for 16 h. After completion of the reaction
(TLC), the reaction mixture was poured into water and extracted
with dichloromethane (3 ꢁ 40 mL), dried over Na2SO4, and con-
centrated in vacuo to give the crude product which was recrystal-
lized from hexane to get the pure product 2. White color solid:
(5.20 g, 88%); m.p.: 758C; 1H NMR: 400 MHz, DMSO-d6: d 3.58–3.59
(m, 4H), 2.63–2.64 (m, 4H), 1.44 (s, 9H); MS: m/z 199.2 (Mþ), 200.2
(Mþ1); Anal. calcd. for C10H17NO3: C, 60.28; H, 8.60; N, 7.03%.
Found: C, 60.20; H, 8.56; N, 7.07%.
Synthesis of tert-butyl 3-(3-cyanobenzyl)-2,4-dioxo-1,3,8-
triazaspiro[4.6]undecane-8-carboxylate (6)
tert-Butyl 2,4-dioxo-1,3,8-triazaspiro[4.6]undecane-8-carboxylate
5 (3.8 g, 13.41 mmol), anhydrous potassium carbonate (2.77 g,
20.11 mmol) and 3-(bromomethyl)benzonitrile (2.89 g, 14.75 mmol)
in acetonitrile (40 mL) were refluxed for 6 h and, after com-
pletion of the reaction (TLC), cooled to room temperature and
filtered. Filtrate was concentrated under vacuum to give the
crude product and it was purified by column chromatography
over silica gel (60–120 mesh) using chloroform/methanol (9:1) as
an eluent to get pure product 6. White color solid: (4.5 g,
84%); m.p.: 2128C; 1H NMR: 400 MHz, DMSO-d6: d 8.90 (s, 1H),
Synthesis of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-
dicarboxylate (3)
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate 2 (5.2 g,
26.10 mmol) and dry diethylether (52 mL) was stirred at
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Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Novel Triazaspirobenzonitriles as Potential Anticonvulsants
205
7.77 (q, J ¼ 1.20 Hz, 1H), 7.76 (d, J ¼ 1.68 Hz, 2H), 7.55–7.55 (m,
2H), 4.56 (s, 2H), 3.28 (t, J ¼ 6.76 Hz, 2H), 3.14 (q, J ¼ 3.80 Hz, 2H),
2.20 (q, J ¼ 10.12 Hz, 2H), 2.07 (q, J ¼ 6.28 Hz, 2H), 1.85
(t, J ¼ 4.72 Hz, 2H), 1.39 (s, 9H); MS: m/z 398.5 (Mþ), 399.5
(Mþ1); Anal. calcd. for C21H26N4O4: C, 63.30; H, 6.58; N,
14.06%. Found: C, 63.25; H, 6.51; N, 14.02%.
3-{[8-(3-Bromophenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (10)
White color solid: (112 mg, 65%); mp ¼ 1948C; 1H NMR:
400 MHz, DMSO-d6: d 8.82 (s, 1H), 7.92 (d, J ¼ 7.44 Hz, 2H),
7.81 (t, J ¼ 6.64 Hz, 1H), 7.76 (d, J ¼ 6.92 Hz, 1H), 7.68 (s, 1H),
7.52–7.61 (m, 3H), 4.57 (s, 2H), 3.60 (q, J ¼ 4.12 Hz, 1H), 3.34 (q,
J ¼ 0.72 Hz, 1H), 3.16 (q, J ¼ 5.88 Hz, 2H), 1.74–1.98 (m, 6H); MS:
m/z 517.4 (Mþ), 518.4 (Mþ1); IR (KBr) 1342 (S O), 1280
–
–
Synthesis of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]-
undec-3-yl)methyl]benzonitrile (7)
(S O) cmꢀ1; Anal. calcd. for C22H21BrN4O4S: C, 51.07; H, 4.09;
N, 10.83%. Found: C, 51.01; H, 4.04; N, 10.80%.
–
–
Dioxane in HCl (50 mL) was mixed with tert-butyl 3-(3-cyanoben-
zyl)-2,4-dioxo-1,3,8-triazaspiro[4.6]undecane-8-carboxylate 6 (4.5 g,
11.29 mmol) and cooled to 08C. Then, the mixture was allowed to
stirred at room temperature for 4 h. After completion of
the reaction (TLC), dioxane was removed under vacuum and
the reaction mixture was neutralized with sodium carbonate
solution, extracted with dichloromethane (3 ꢁ 50 mL). Dried
over Na2SO4 and concentrated in vacuo to get pure product 7.
White color solid: (2.8 g, 83%); m.p.: 1988C; 1H NMR: 400 MHz,
DMSO-d6: 400 MHz, DMSO-d6: d 8.90 (s, 1H), 8.72 (s, 1H), 7.77 (q,
J ¼ 1.20 Hz, 1H), 7.76 (d, J ¼ 1.68 Hz, 2H), 7.55–7.55 (m, 2H), 4.56
(s, 2H), 3.28 (t, J ¼ 6.76 Hz, 1H), 3.14 (q, J ¼ 3.80 Hz, 3H), 2.20 (q,
J ¼ 10.12 Hz, 1H), 2.07 (q, J ¼ 6.28 Hz, 2H), 1.85 (t, J ¼ 4.72 Hz,
3H); MS: m/z 298.3 (Mþ), 299.3 (Mþ1); Anal. calcd. for C16H18N4O2:
C, 64.41; H, 6.08; N, 18.78%. Found: C, 64.37; H, 6.01; N, 18.72%.
3-{[8-(2-Fluorophenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (11)
White color solid: (106 mg, 69%); mp ¼ 1888C; 1H NMR:
400 MHz, DMSO-d6: d 8.85 (s, 1H), 7.83 (d, J ¼ 7.28 Hz, 1H),
7.68–7.80 (m, 3H), 7.47–7.58 (m, 3H), 7.41 (t, J ¼ 7.68 Hz, 1H),
4.57 (s, 2H), 3.62 (q, J ¼ 4.00 Hz, 1H), 3.45 (q, J ¼ 0.72 Hz, 1H),
3.24 (q, J ¼ 7.24 Hz, 2H), 1.74–1.99 (m, 6H); MS: m/z 456.5 (Mþ),
457.5 (Mþ1); IR (KBr) 1347 (S O), 1283 (S O) cmꢀ1; Anal. calcd.
–
–
–
–
for C22H21FN4O4S: C, 57.88; H, 4.64; N, 12.27%. Found: C, 57.81; H,
4.58; N, 12.20%.
3-{[8-(2,5-Dimethylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (12)
White color solid: (107 mg, 68%); mp ¼ 1808C; 1H NMR:
400 MHz, DMSO-d6: d 8.84 (s, 1H), 7.76 (d, J ¼ 6.76 Hz, 1H),
7.68 (s, 1H), 7.56 (t, J ¼ 9.76 Hz, 3H), 7.34 (q, J ¼ 7.76 Hz, 2H),
4.58 (s, 2H), 3.59 (q, J ¼ 4.76 Hz, 1H), 3.29–3.38 (m, 1H), 3.23 (q,
General procedure for the synthesis of triazaspiro
sulfonamides (8–22)
The reactants such as 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-
yl)methyl]benzonitrile 7 (100 mg 0.33 mmol), triethylamine
(50.88 mg, 0.50 mmol), and sulfonyl chloride (0.37 mmol) in
dichloromethane (4 mL) were mixed and stirred at room
temperature for 16 h. After completion of the reaction (TLC),
it was quenched with saturated sodium bicarbonate solution,
extracted with dichloromethane (3 ꢁ 4 mL), dried over Na2SO4
and concentrated in vacuo to give the crude product which was
purified by column chromatography on silica employing
dichloromethane/methanol (9:1) as an eluent to obtain pure
white solid (8–22).
J ¼ 8.24 Hz,þ2H), 2.47 (s, 3H), 2.34 (s, 3H), 1.78–1.98 (m, 6H); MS:
ꢀ1
–
–
–
m/z 466.6 (M ), 467.6 (Mþ1); IR (KBr) 1336 (S O), 1278 (S O) cm
;
–
Anal. calcd. for C24H26N4O4S: C, 61.78; H, 5.62; N, 12.01%. Found:
C, 61.70; H, 5.56; N, 12.04%.
3-{[8-(2-Methylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (13)
White color solid: (105 mg, 69%); mp ¼ 1828C; 1H NMR:
400 MHz, DMSO-d6: d 8.87 (s, 1H), 7.77 (s, 3H), 7.53–7.58 (m,
3H), 7.38–7.45 (m, 2H), 4.58 (s, 2H), 3.60 (q, J ¼ 4.12 Hz, 1H),
3.34 (q, J ¼ 0.72 Hz, 1H), 3.16 (q, J ¼ 5.88 Hz, 2H), 2.34 (s, 3H),
1.74–1.98 (m, 6H); MS: m/z 452.5 (Mþ), 453.5 (Mþ1); IR (KBr) 1345
3-{[8-(3,4-Dimethylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (8)
(S O), 1284 (S O) cmꢀ1; Anal. calcd. for C23H24N4O4S: C, 61.05; H,
–
–
–
–
White color solid: (104 mg, 67%); mp ¼ 1828C; 1H NMR:
400 MHz, DMSO-d6: d 7.76 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H),
7.48–7.57 (m, 4H), 7.37 (d, J ¼ 8.08 Hz, 1H), 4.56 (s, 2H),
3.32–3.54 (m, 1H), 3.20 (s, 1H), 3.07 (q, J ¼ 9.48 Hz, 2H), 2.30
(d, J ¼ 2.32 Hz, 6H), 1.70–2.05 (m, 6H); MS: m/z 466.6 (Mþ),
5.35; N, 12.38%. Found: C, 61.01; H, 5.30; N, 12.31%.
3-{[8-(3-Chlorophenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (14)
467.6 (Mþ1); IR (KBr) 1344 (S O), 1281 (S O) cmꢀ1; Anal. calcd.
White color solid: (108 mg, 68%); mp ¼ 1988C; 1H NMR:
400 MHz, DMSO-d6: d 8.82 (s, 1H), 7.81 (d, J ¼ 1.64 Hz, 1H),
7.75–7.80 (m, 3H), 7.66 (q, J ¼ 7.88 Hz, 2H), 7.55 (d,
J ¼ 7.04 Hz, 2H), 4.57 (s, 2H), 3.60 (q, J ¼ 3.80 Hz, 1H), 3.36 (q,
–
–
–
–
for C24H26N4O4S: C, 61.78; H, 5.62; N, 12.01%. Found: C, 61.78; H,
5.62; N, 12.01%.
J ¼ 9.20 Hz,þ1H), 3.16 (q, J ¼ 10.40 Hz, 2H), 1.74–1.98 (m, 6H); MS:
3-{[8-(2-Methylphenyl)sulfonyl-2,4-dioxo-1,3,8-
ꢀ1
–
–
–
m/z 472.9 (M ), 474 (Mþ1); IR (KBr) 1341 (S O), 1282 (S O) cm
;
–
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (9)
Anal. calcd. for C22H21ClN4O4S: C, 55.87; H, 4.48; N, 11.85%.
Found: C, 55.87; H, 4.48; N, 11.85%.
White color solid: (101 mg, 67%); mp ¼ 1808C; 1H NMR:
400 MHz, DMSO-d6: d 8.86 (s, 1H), 7.77 (s, 3H), 7.53–7.58
(m, 3H), 7.38–7.45 (m, 2H), 4.58 (s, 2H), 3.23–3.58 (m, 4H), 2.53
(s, 3H), 1.79–1.99 (m, 6H); MS: m/z 452.5 (ꢀM1þ), 453.5 (Mþ1);
3-{[8-(4-Fluoro-2-methylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (15)
–
–
–
IR (KBr) 1345 (S O), 1284 (S O) cm
;
Anal. calcd.
–
White color solid: (111 mg, 70%); mp ¼ 1928C; 1H NMR:
400 MHz, DMSO-d6: d 8.86 (s, 1H), 7.81–7.85 (m, 1H), 7.74–7.77
for C23H24N4O4S: C, 61.05; H, 5.35; N, 12.38%. Found: C, 61.01;
H, 5.33; N, 12.32%.
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206
M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
(m, 2H), 7.68 (q, J ¼ 6.52 Hz, 2H), 7.56 (t, J ¼ 7.00 Hz, 2H), 4.58 (s,
2H), 3.57 (d, J ¼ 3.76 Hz, 1H), 3.32 (q, J ¼ 4.80 Hz, 1H), 3.25 (q,
J ¼þ8.00 Hz, 2H), 2.53 (s, 3H), 1.78–1.99 (m, 6H); MS: m/z 470.5
for C24H26N4O4S: C, 61.78; H, 5.62; N, 12.01%. Found: C, 61.72;
H, 5.67; N, 12.06%.
(M ), 471.5 (Mþ1); IR (KBr) 1346 (S O), 1287 (S O) cmꢀ1; Anal.
–
–
–
–
3-{[8-(3-Methylphenyl)sulfonyl-2,4-dioxo-1,3,8-
calcd. for C23H23FN4O4S: C, 58.71; H, 4.93; N, 11.91%. Found: C,
58.65; H, 4.90; N, 11.84%.
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (21)
White color solid: (103 mg, 68%); mp ¼ 1818C; 1H NMR:
400 MHz, DMSO-d6: d 8.82 (s, 1H), 7.78 (t, J ¼ 1.40 Hz, 1H), 7.74
(q, J ¼ 8.32 Hz, 1H), 7.50–7.61 (m, 6H), 4.58 (s, 2H), 3.56 (q,
J ¼ 3.84 Hz, 1H), 3.33 (d, J ¼ 6.64 Hz, 1H), 3.12 (q, J ¼ 9.12 Hz,
2H), 2.39 (s, 3H), 1.73–1.98 (m, 6H); MS: m/z 452.5 (Mþ), 453.5
3-{[8-(4-Methoxyphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (16)
White color solid: (107 mg, 68%); mp ¼ 1848C; 1H NMR:
400 MHz, DMSO-d6: d 8.80 (s, 1H), 7.72 (q, J ¼ 13.88 Hz, 3H),
7.67 (s, 1H), 7.54 (q, J ¼ 9.08 Hz, 2H), 7.13 (d, J ¼ 8.68 Hz, 2H),
4.56 (s, 2H), 3.84 (s, 3H), 3.52 (q, J ¼ 5.32 Hz, 1H), 3.29 (q,
(Mþ1); IR (KBr) 1345 (S O), 1284 (S O) cmꢀ1; Anal. calcd.
–
–
–
for C23H24N4O4S: C, 61.05; H, 5.35; N, 12.38%. Found: C, 60.92;
–
H, 5.30; N, 12.32%.
J ¼ 8.48 Hz, 1H), 3.14 (q, J ¼ 9.40 Hz, 2H), 1.71–1.96 (m, 6H);
þ
–
MS: m/z 468.5 (M ), 469.5 (Mþ1); IR (KBr) 1340 (S O), 1281
–
3-{[8-(2-Cyanophenyl)sulfonyl-2,4-dioxo-1,3,8-
(S O) cmꢀ1; Anal. calcd. for C23H24N4O5S: C, 58.96; H, 5.16; N,
11.96%. Found: C, 58.91; H, 5.10; N, 11.93%.
–
–
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (22)
White color solid: (101mg, 65%); mp ¼ 2248C; 1H NMR: 400 MHz,
DMSO-d6: d 8.84 (s, 1H), 7.81 (d, J ¼ 1.64 Hz, 1H), 7.75–7.80 (m, 3H),
7.66 (q, J ¼ 7.88 Hz, 2H), 7.55 (d, J ¼ 7.04 Hz, 2H), 4.58 (s, 2H), 3.60
(q, J ¼ 3.80 Hz, 1H), 3.36 (q, J ¼ 9.20 Hz, 1H), 3.16 (q, J ¼ 10.40 Hz,
2H), 1.74–1.99 (m, 6H); MS: ꢀm1/z 463.5 (Mþ), 464.5 (Mþ1); IR (KBr)
3-{[8-(4-Methylbenzyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (17)
White color solid: (98 mg, 63%); mp ¼ 1828C; 1H NMR: 400 MHz,
DMSO-d6: d 8.83 (s, 1H), 7.92 (d, J ¼ 7.44 Hz, 2H), 7.81 (t,
J ¼ 6.64 Hz, 1H), 7.76 (d, J ¼ 6.92 Hz, 1H), 7.67 (s, 1H),
7.52–7.61 (m, 3H), 4.57 (s, 2H), 4.22 (s, 2H), 3.60 (q, J ¼ 4.12 Hz,
1H), 3.34 (q, J ¼ 0.72 Hz, 1H), 3.16 (q, J ¼ 5.88 Hz, 2H), 2.34 (s, 3H),
1.73–1.97 (m, 6H); MS: m/z 466.6 (Mþ), 467.6 (Mþ1); IR (KBr) 1337
–
–
–
1341 (S O), 1282 (S O) cm ; Anal. calcd. for C23H21N5O4S: C,
–
59.60; H, 4.57; N, 15.11%. Found: C, 59.56; H, 4.51; N, 15.09%.
General procedure for the synthesis of triazaspiro
carboxylate (23–37)
A mixture of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)-
methyl]benzonitrile 7 (100 mg 0.33 mmol), triethylamine
(S O), 1277 (S O) cmꢀ1; Anal. calcd. for C24H26N4O4S: C, 61.78; H,
–
–
–
–
5.62; N, 12.01%. Found: C, 61.71; H, 5.67; N, 12.04%.
(50.88 mg, 0.50 mmol) and acid chloride (0.37 mmol) in
dichloromethane (4 mL) was stirred at room temperature for
16 h. After completion of the reaction (TLC) , it was quenched
with saturated sodium bicarbonate solution, extracted with
dichloromethane (3 ꢁ 4 mL), dried over Na2SO4 and concen-
trated in vacuo to give the crude product which was purified
by column chromatography on silica employing dichlorome-
thane/methanol (9:1) as an eluent to obtain pure white solid
(23–37).
3-{[8-(3-Fluorophenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (18)
White color solid: (102 mg, 67%); mp ¼ 1898C; 1H NMR: 400 MHz,
DMSO-d6: d 8.82 (s, 1H), 7.75 (d, J ¼ 6.84 Hz, 1H), 7.68–7.73 (m, 2H),
7.62–7.65 (m, 2H), 7.52–7.60 (m, 3H), 4.57 (s, 2H), 3.59 (q,
J ¼ 3.84 Hz, 1H), 3.35 (q, J ¼ 8.92 Hz, 1H), 3.16 (t, J ¼ 13.28 Hz,
2H), 1.73–1.98 (m, 6H);); MS: m/z 456.5 (Mþ), 457.5 (Mþ1); IR (KBr)
1347 (S O), 1283 (S O) cmꢀ1; Anal. calcd. for C22H21FN4O4S: C,
–
–
–
–
57.88; H, 4.64; N, 12.27%. Found: C, 57.82; H, 4.57; N, 12.22%.
(2-Chlorobenzyl)-3-(3-cyanobenzyl)-2,4-dioxo-1,3,8-
3-{[8-(3,5-Dimethylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undecane-8-carboxylate (23)
White color solid: (106 mg, 68%); mp ¼ 1028C; 1H NMR:
400 MHz, DMSO-d6: d 8.94 (s, 1H), 7.77 (d, J ¼ 1.48 Hz, 1H),
7.74 (t, J ¼ 23.40 Hz, 1H), 7.48–7.57 (m, 4H), 7.38 (q,
J ¼ 2.28 Hz, 2H), 5.17 (s, 2H), 4.59 (s, 2H), 3.60 (q, J ¼ 4.12 Hz,
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (19)
White color solid: (105 mg, 67%); mp ¼ 1808C; 1H NMR:
400 MHz, DMSO-d6: d 8.86 (s, 1H), 7.76 (d, J ¼ 6.76 Hz, 1H),
7.67 (s, 1H), 7.56 (t, J ¼ 9.76 Hz, 3H), 7.34 (q, J ¼ 7.76 Hz, 2H),
4.56 (s, 2H), 3.59 (q, J ¼ 4.76 Hz, 1H), 3.29–3.38 (m, 1H), 3.23 (q,
1H), 3.34 (q, J ¼ 0.72 Hz, 1H), 3.16 (q, J ¼ 5.88 Hz, 2H), 1.74–1.98
þ
–
–
J ¼ 8.24 Hz,þ2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.78–1.98 (m, 6H); MS:
(m, 6H); MS: m/z 432.5 (M ), 433.5 (Mþ1); IR (KBr) 1670 (C O)
ꢀ1
–
–
–
m/z 466.6 (M ), 467.6 (Mþ1); IR (KBr) 1336 (S O), 1278 (S O) cm
;
cmꢀ1; Anal. calcd. for C24H24N4O4: C, 66.65; H, 5.59; N, 12.96%.
Found: C, 66.60; H, 5.54; N, 12.91%.
–
Anal. calcd. for C24H26N4O4S: C, 61.78; H, 5.62; N, 12.01%. Found:
C, 61.71; H, 5.57; N, 12.04%.
(4-Chlorophenyl)-3-(3-cyanobenzyl)-2,4-dioxo-1,3,8-
3-{[8-(4-Ethylphenyl)sulfonyl-2,4-dioxo-1,3,8-
triazaspiro[4.6]undecane-8-carboxylate (24)
White color solid: (99 mg, 65%); mp ¼ 2048C; 1H NMR: 400 MHz,
DMSO-d6: d 8.96 (s, 1H), 7.78 (d, J ¼ 1.60 Hz, 1H), 7.75 (t,
J ¼ 11.40 Hz, 2H), 7.49–7.58 (m, 3H), 7.38 (q, J ¼ 2.28 Hz, 2H),
4.58 (s, 2H), 3.60 (q, J ¼ 4.12 Hz, 1H), 3.34 (q, J ¼ 0.72 Hz, 1H),
3.16 (q, J ¼ 5.88 Hz, 2H), 1.74–1.98 (m, 6H); MS: m/z 452.9 (Mþ),
–
triazaspiro[4.6]undec-3-yl]methyl}benzonitrile (20)
White color solid: (99 mg, 63%); mp ¼ 1848C; 1H NMR: 400 MHz,
DMSO-d6: d 8.81 (s, 1H), 7.77 (d, J ¼ 7.00 Hz, 1H), 7.70 (t,
J ¼ 3.76 Hz, 3H), 7.52–7.58 (m, 2H), 00007.46 (d, J ¼ 8.20 Hz,
2H), 4.57 (s, 2H), 3.54 (q, J ¼ 3.80 Hz, 1H), 3.33 (t, J ¼ 12.84 Hz,
1H), 3.11 (q, J ¼ 8.52 Hz, 2H), 2.55 (q, J ¼ 1.68 Hz, 2H), 1.73–1.97
(m, 6H), 1.21 (t, J ¼ 7.60 Hz, 3H); MS: m/z 466.6 (Mþ), 467.6 (Mþ1);
454 (Mþ1); IR (KBr) 1675 (C O) cmꢀ1
;
Anal. calcd.
–
for C23H21ClN4O4: C, 61.00; H, 4.67; N, 12.37%. Found: C,
61.09; H, 4.61; N, 12.33%.
IR (KBr) 1337 (S O), 1277 (S O) cmꢀ1
;
Anal. calcd.
–
–
–
–
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www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
Novel Triazaspirobenzonitriles as Potential Anticonvulsants
207
1667 (C O) cmꢀ1; Anal. calcd. for C23H22N4O3: C, 68.64; H, 5.51;
–
N, 13.92%. Found: C, 68.57; H, 5.45; N, 13.90%.
–
3-[(2,4-Dioxo-8-(4-methylphenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (25)
White color solid: (101 mg, 72%); mp ¼ 1868C; 1H NMR:
400 MHz, DMSO-d6: d 8.96 (s, 1H), 7.76 (d, J ¼ 6.52 Hz, 1H),
7.69 (d, J ¼ 6.96 Hz, 1H), 7.55 (t, J ¼ 9.76 Hz, 2H), 7.30 (d,
J ¼ 7.84 Hz, 2H), 7.23 (d, J ¼ 7.84 Hz, 2H), 4.59 (s, 2H),
3.58–3.68 (m, 1H), 3.39–3.42 (m, 1H), 3.32–3.38 (m, 2H), 2.33 (s,
3H), 1.71–1.86 (m, 6H); MS: m/z 416.5 (Mþ), 417.5 (Mþ1); IR (KBr)
3-[(2,4-Dioxo-8-(3-fluorophenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (31)
White color solid: (100 mg, 71%); mp ¼ 1968C; 1H NMR:
400 MHz, DMSO-d6: d 8.88 (s, 1H), 7.76 (t, J ¼ 6.48 Hz, 1H), 7.68
(d, J ¼ 9.20 Hz, 1H), 7.46–7.56 (m, 3H), 7.25 (q, J ¼ 5.52 Hz, 3H),
4.59 (s, 2H), 3.89 (d, J ¼ 11.84 Hz, 1H), 3.57 (q, J ¼ 4.00 Hz, 1H),
3.36 (q, J ¼ 5.52 Hz, 2H), 1.71–1.92 (m, 6H); MS: m/z 420.5 (Mþ),
–
1677 (C O) cmꢀ1; Anal. calcd. for C24H24N4O3: C, 69.21; H, 5.81;
–
–
N, 13.45%. Found: C, 69.17; H, 5.74; N, 13.40%.
421.5 (Mþ1); IR (KBr) 1672 (C O) cmꢀ1
; Anal. calcd.
–
for C23H21FN4O3: C, 65.70; H, 5.03; N, 13.33%. Found: C, 65.67;
H, 5.07; N, 13.27%.
3-[(2,4-Dioxo-8-(benzylmethyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (26)
White color solid: (94 mg, 67%); mp ¼ 1898C; 1H NMR: 400 MHz,
DMSO-d6: d 8.98 (s, 1H), 7.77 (d, J ¼ 8.00 Hz, 1H), 7.69 (d,
J ¼ 4.00 Hz, 1H), 7.57 (q, J ¼ 4.00 Hz, 2H), 7.39–7.45 (m, 5H),
4.60 (s, 2H), 3.70 (s, 2H), 3.59–3.69 (m, 1H), 3.39–3.42 (m, 1H),
3.32–3.41 (m, 2H), 1.79–1.89 (m, 6H); MS: m/z 416.5 (Mþ), 417.5
3-[(2,4-Dioxo-8-(4-fluorophenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (32)
White color solid: (96 mg, 68%); mp ¼ 1958C; 1H NMR: 400 MHz,
DMSO-d6: d 8.87 (s, 1H), 7.76 (d, J ¼ 5.20 Hz, 2H), 7.68 (d,
J ¼ 7.16 Hz, 2H), 7.47–7.56 (m, 2H), 7.26 (t, J ¼ 8.84 Hz, 2H),
4.59 (s, 2H), 3.90 (d, J ¼ 18.04 Hz, 1H), 3.44 (d, J ¼ 13.64 Hz, 1H),
3.28–3.41 (m, 2H), 1.72–1.87 (m, 6H); MS: m/z 420.5 (Mþ), 421.5
(Mþ1); IR (KBr) 1658 (C O) cmꢀ1; Anal. calcd. for C24H24N4O3: C,
–
–
69.21; H, 5.81; N, 13.45%. Found: C, 69.14; H, 5.70; N, 13.41%.
(Mþ1); IR (KBr) 1675 (C O) cmꢀ1; Anal. calcd. for C23H21FN4O3: C,
–
–
65.70; H, 5.03; N, 13.33%. Found: C, 65.69; H, 5.01; N, 13.29%.
3-[(2,4-Dioxo-8-(2-fluorophenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (27)
White color solid: (100 mg, 71%); mp ¼ 1958C; 1H NMR:
400 MHz, DMSO-d6: d 8.98 (s, 1H), 7.67–7.78 (m, 2H), 7.46–7.57
(m, 3H), 7.38–7.42 (m, 1H), 7.27–7.32 (m, 2H), 4.60 (s, 2H),
3.57–3.67 (m, 1H), 3.34–3.40 (m, 1H), 3.31–3.32 (m, 2H),
1.72–1.89 (m, 6H); MS: m/z 420.4 (Mþ), 421.4 (Mþ1); IR (KBr)
(Phenyl)-3-(3-cyanobenzyl)-2,4-dioxo-1,3,8-
triazaspiro[4.6]undecane-8-carboxylate (33)
White color solid: (102 mg, 73%); mp ¼ 1878C; 1H NMR:
400 MHz, DMSO-d6: d 8.96 (s, 1H), 7.76 (d, J ¼ 6.44 Hz, 1H),
7.69 (d, J ¼ 9.12 Hz, 1H), 7.54 (q, J ¼ 6.96 Hz, 2H), 7.39–7.45
(m, 5H), 4.58 (s, 2H), 3.59–3.69 (m, 1H), 3.39–3.41 (m, 1H),
3.32–3.36 (m, 2H), 1.74–1.89 (m, 6H); MS: m/z 418.4 (Mþ), 419.4
1671 (C O) cmꢀ1; Anal. calcd. for C23H21FN4O3: C, 65.70; H,
–
–
5.03; N, 13.33%. Found: C, 65.67; H, 5.06; N, 13.26%.
(Mþ1); IR (KBr) 1667 (C O) cmꢀ1; Anal. calcd. for C23H22N4O4: C,
–
–
66.02; H, 5.30; N, 13.39%. Found: C, 66.06; H, 5.25; N, 13.31%.
3-[(2,4-Dioxo-8-(3-methylphenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (28)
White color solid: (98 mg, 70%); mp ¼ 1878C; 1H NMR: 400 MHz,
DMSO-d6: d 8.99 (s, 1H), 7.76 (d, J ¼ 6.52 Hz, 1H), 7.69 (d,
J ¼ 6.96 Hz, 1H), 7.55 (t, J ¼ 9.76 Hz, 2H), 7.30 (d, J ¼ 7.84 Hz,
2H), 7.23 (d, J ¼ 7.84 Hz, 2H), 4.60 (s, 2H), 3.58–3.69 (m, 1H),
3.39–3.43 (m, 1H), 3.33–3.37 (m, 2H), 2.41 (s, 3H), 1.70–1.89 (ꢀm1,
3-[(2,4-Dioxo-8-(4-chlorophenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (34)
White color solid: (99 mg, 68%); mp ¼ 1998C; 1H NMR: 400 MHz,
DMSO-d6: d 8.96 (s, 1H), 7.76 (d, J ¼ 5.60 Hz, 1H), 7.68 (d,
J ¼ 7.88 Hz, 1H), 7.55 (d, J ¼ 6.80 Hz, 1H), 7.50 (d, J ¼ 8.40 Hz,
3H), 7.43 (q, J ¼ 8.60 Hz, 2H), 4.59 (s, 2H), 3.89 (d, J ¼ 14.44 Hz,
1H), 3.40 (d, J ¼ 10.00 Hz, 1H), 3.30 (d, J ¼ 19.68 Hz, 2H),
1.71–1.87 (m, 6H); MS: m/z 436.9 (Mþ), 438 (Mþ1); IR (KBr)
þ
–
6H); MS: m/z 416.5 (M ), 417.5 (Mþ1); IR (KBr) 1677 (C O) cm
;
–
Anal. calcd. for C24H24N4O3: C, 69.21; H, 5.81; N, 13.45%. Found:
C, 69.18; H, 5.77; N, 13.40%.
1679 (C O) cmꢀ1; Anal. calcd. for C23H21ClN4O3: C, 63.23; H,
–
–
3-[(2,4-Dioxo-8-(3-chlorophenyloyl)-1,3,8-
4.84; N, 12.82%. Found: C, 63.16; H, 4.77; N, 12.79%.
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (29)
White color solid: (103 mg, 70%); mp ¼ 1988C; 1H NMR:
400 MHz, DMSO-d6: d 8.95 (s, 1H), 7.76 (d, J ¼ 6.64 Hz, 1H),
7.73 (d, J ¼ 22.72 Hz, 1H), 7.54 (q, J ¼ 6.84 Hz, 4H), 7.48 (d,
J ¼ 10.40 Hz, 1H), 7.37 (d, J ¼ 7.36 Hz, 1H), 4.60 (s, 2H),
3.58–3.68 (m, 1H), 3.41–3.44 (m, 1H), 3.32–3.33 (m, 2H),
1.78–1.89 (m, 6H); MS: m/z 436.9 (Mþ), 438 (Mþ1); IR (KBr)
3-[(2,4-Dioxo-8-(2-trifluoromethylphenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (35)
White color solid: (108 mg, 68%); mp ¼ 2148C; 1H NMR:
400 MHz, DMSO-d6: d 8.96 (s, 1H), 7.84 (d, J ¼ 56.72 Hz, 1H),
7.68 (d, J ¼ 8.32 Hz, 1H), 7.55 (d, J ¼ 6.80 Hz, 2H), 7.50 (d,
J ¼ 8.40 Hz, 2H), 7.43 (q, J ¼ 8.60 Hz, 2H), 4.59 (s, 2H), 3.95
(d, J ¼ 13.96 Hz, 1H), 3.40 (d, J ¼ 13.20 Hz, 1H), 3.31 (d,
J ¼ 11.76 Hz, 2H), 1.69–1.87 (m, 6H); MS: m/z 470.4 (Mþ), 471.4
1679 (C O) cmꢀ1; Anal. calcd. for C23H21ClN4O3: C, 63.23; H,
–
–
4.84; N, 12.82%. Found: C, 63.18; H, 4.79; N, 12.76%.
(Mþ1); IR (KBr) 1680 (C O) cmꢀ1; Anal. calcd. for C24H21F3N4O3: C,
–
–
3-[(2,4-Dioxo-8-(phenyloyl)-1,3,8-triazaspiro[4.6]undec-3-
61.27; H, 4.50; N, 11.91%. Found: C, 61.21; H, 4.47; N, 11.86%.
yl)methyl]benzonitrile (30)
White color solid: (97 mg, 72%); mp ¼ 1818C; 1H NMR: 400 MHz,
DMSO-d6: d 8.97 (s, 1H), 7.76 (d, J ¼ 6.44 Hz, 1H), 7.69 (d,
J ¼ 9.12 Hz, 1H), 7.54 (q, J ¼ 6.96 Hz, 2H), 7.38–7.44 (m, 5H),
4.59 (s, 2H), 3.59–3.68 (m, 1H), 3.39–3.42 (m, 1H), 3.32–3.35 (m,
2H), 1.73–1.89 (m, 6H); MS: m/z 402.4 (Mþ), 403.4 (Mþ1); IR (KBr)
3-[(2,4-Dioxo-8-(2-chlorophenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (36)
White color solid: (98 mg, 67%); mp ¼ 1998C; 1H NMR: 400 MHz,
DMSO-d6: d 8.95 (s, 1H), 7.77 (d, J ¼ 1.28 Hz, 1H), 7.68 (d,
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www.archpharm.com

208
M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209
J ¼ 12.76 Hz, 2H), 7.56 (d, J ¼ 6.80 Hz, 2H), 7.42–7.53 (m, 3H),
4.59 (s, 2H), 4.00 (d, J ¼ 6.84 Hz, 1H), 3.35 (d, J ¼ 16.40 Hz, 1H),
3.22–3.26 (m, 2H), 1.69–1.89 (m, 6H); MS: m/z 436.9 (Mþ), 438
the biological responses in 50% of animals; neurotoxicity was
expressed as the median toxic dose (TD50). Groups of six mice
each were given a range of i.p. doses of the selected drug until at
least four points were established in the range of 10–90% seizure
protection or minimal observed neurotoxicity [36]. From the plot
of these data, the respective ED50 and TD50 values, slope of the
regression line, and standard error of the slope were calculated
by means of a computer program based on the method described
by Finney [37].
(Mþ1); IR (KBr) 1679 (C O) cmꢀ1; Anal. calcd. for C23H21ClN4O3:
–
–
C, 63.23; H, 4.84; N, 12.82%. Found: C, 63.16; H, 4.77; N, 12.79%.
3-[(2,4-Dioxo-8-(4-tert-butylphenyloyl)-1,3,8-
triazaspiro[4.6]undec-3-yl)methyl]benzonitrile (37)
White color solid: (104 mg, 68%); mp ¼ 1928C; 1H NMR:
400 MHz, DMSO-d6: d 8.97 (s, 1H), 7.86 (d, J ¼ 8.48 Hz, 1H),
7.76 (d, J ¼ 6.44 Hz, 1H), 7.69 (s, 1H), 7.56 (t, J ¼ 6.68 Hz, 1H),
7.51 (d, J ¼ 8.52 Hz, 1H), 7.48 (d, J ¼ 36.96 Hz, 1H), 7.32 (t,
J ¼ 12.40 Hz, 2H), 4.59 (s, 2H), 3.91 (d, J ¼ 17.00 Hz, 1H), 3.41
(d, J ¼ 19.28 Hz, 1H), 3.33–3.35 (m, 2H), 1.73–1.86 (m, 6H), 1.28ꢀ(1s,
The authors are grateful to
G Pullareddy College of Pharmacy,
Mehdipatnam, Hyderabad, India for providing facilities to carry out
the anticonvulsant activity assessment. One the authors, M.M., is
grateful to the University of Mysore, Mysore for providing the necessary
facilities.
þ
–
9H); MS: m/z 470.4 (M ), 471.4 (Mþ1); IR (KBr) 1669 (C O) cm
;
–
Anal. calcd. for C24H21F3N4O3: C, 61.27; H, 4.50; N, 11.91%. Found:
C, 61.24; H, 4.47; N, 11.88%.
The authors have declared no conflict of interest.
Pharmacology
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